Targeted SiRNA Inhibition of Vascular Endothelial Growth Factors in Lung Cancer Cells

Shuhua Bai, Ph.D.
Husson University, Bangor

Vascular endothelial growth factor (VEGF) plays a crucial role in cancer cell growth and tumor expansion. Inhibition of VEGF overexpression offers a potential target for cancer therapy. Dr. Bai will identify nanoparticle based small interfering RNAs (SiRNAs) for targeting prevention of VEGF expression in lung tumors. This work will aim at providing important new data on a safe and effective therapeutic approach to lung cancer using gene therapy and nanotechnology to improve the effectiveness of the treatment efficacy while limiting the toxicity. In addition, this work will help develop general principles that can be applied toward the establishment of nanoparticles as a platform technology for delivering targeted gene silencing therapies against other cancers.

Validating Prediction Tools for Prostate Cancer Quality of Life Outcomes

Amy Haskins, Ph.D.
Maine Medical Center

Decisions about prostate cancer treatment are difficult because of the risks of developing sexual and urinary problems. This study intends to refine and validate a model that predicts problems encountered by prostate cancer patients after treatment. Using 10 years of clinical data, Dr. Haskins’ goal is to derive more accurate, tailored information on risks of side effects based on a patient’s personal characteristics prior to treatment. Ultimately her research team hopes this prediction tool will provide patients and clinicians with valuable information to help inform treatment decisions.

The Molecular Structure of Arm 1

Derek Hoelz, Ph.D.
Maine Institute for Human Genetics and Health

Dr. Derek Hoeltz and the Maine Institute for Human Genetics and Health laboratory have identified a new gene (Arm1) with important cancer-related functions. While chemotherapy is effective in destroying cancer cells, the side-effects of the drugs result from the killing of non-cancer tissues. When Dr. Hoelz’s research team reduced expression of the Arm1 gene, cancer cells became more responsive to chemotherapy. Remarkably, in cells with a functional p53 gene, which is found mutated in >50% of all cancers, they observed the opposite effects – it protected the cells from chemotherapy. Inhibition of Arm1 appears to be an attractive approach to treating cancer patients, increasing the effectiveness of chemotherapeutics by enhancing their ability to kill off cancer cells while protecting healthy surrounding tissues from their detrimental effects, reducing side-effects. This research grant will help Dr. Hoelz’s team take the initial steps in the development of Arm1 inhibitors to be used as chemotherapeutics. In order to accomplish these goals, they have teamed with the laboratory of Dr. Jeff Perry at the Scripps Research Institute in La Jolla, to investigate Arm1’s molecular structure in high detail. The results of these studies will allow them to identify and test Arm1 inhibitors that may ultimately be used to more effectively treat cancer.

Notch Regulation of the Tumor Suppressor miR-145 in Breast Cancer Cells

Lucy Liaw, Ph.D.
Maine Medical Center

Tumor suppressors are protective genes that normally function to inhibit cancer. Recently, a class of genes encoding small RNA molecules, called microRNAs, have been shown to regulate tumor growth. When levels of a tumor suppressor are decreased, cells are more susceptible to becoming cancer. Dr. Liaw’s project focuses on one microRNA, miR-145, which is typically suppressed during cancer. The goal of this project is to understand what activates miR-145 in human breast cancer cells. Dr. Liaw’s research team identified an upstream signaling regulator, called the Notch pathway. Their aim is to understand how Notch activates miR-145 and therefore potentially restore its tumor suppressive activity to inhibit breast cancer growth.

Imaging Glioma Stem Cell Dynamics in Vivo

Da-Ting Lin, Ph.D.
The Jackson Laboratory

Eliminating cancer relapse will be crucial for winning our fight against cancer. Cancer stem cells are thought to underlie cancer relapse following radiation or chemotherapy. Dr. Lin’s research team will use in vivo two-photon microscopy to determine whether the physical association between glioma stem cells and the vascular endothelial cells are critical in tumor initiation and in tumor relapse. Their study is likely to offer important insights into early stages of tumor initiation from cancer stem cells, paving the way for future efforts in targeting cancer stem cells as therapeutic strategies for cancer treatment.

Functional Analysis of Foxq1's Role in Tumor Vascularization

Antonia Planchart, Ph.D.
Mount Dessert Biological Laboratory

Tumor growth relies on access to the circulatory system, which it achieves by a process called angiogenesis. The resulting vascularization of the tumor provides the necessary nutrients for growth and spread (i.e., metastasis) to other regions of the body. Understanding the molecular basis of angiogenesis is an important area of cancer research. Foxq1 is a nuclear protein that is misregulated in several human cancers and Dr. Planchart’s work in zebrafish has uncovered a potential role for Foxq1 in regulating angiogenesis. Mount Desert Biological Laboratory is taking advantage of the transparency of zebrafish embryos to visualize angiogenesis in real time, in order to understand the role of Foxq1 in this process. Their long-term objective is to understand the molecular pathways leading to tumor vascularization in order to develop strategies to block it, thus starving the tumor and preventing its spread.

FGF Export from Endothelial Cells: Protumorigenic Potential and Methods of Regulation

Igor Prudovsky, Ph.D., DSc
Maine Medical Center

Small vessels that feed solid tumors are different from normal blood capillaries. The endothelial cells of these vessels produce large amounts of secreted regulatory proteins. These proteins may stimulate the growth of tumor cells and make tumors more aggressive. Dr. Prudovsky’s research team will explore the effect of the potent growth factor FGF1 produced and secreted by endothelial cells on tumor growth and metastasis. They will also study the ways to inhibit the growth of tumors by blocking FGF1 export from tumor vessels.

Inceptive Role of miR-199b in Acute Myeloid Leukemia

Pradeep Sathyanarayana, Ph.D.
Maine Medical Center

Dr. Sathyanarayana is addressing acute myeloid leukemia (AML), seeking to define the role of certain biomarkers in the disease. One of the major objectives of his work is the development of novel prognostic factors including microRNAs. Dr. Sathyanarayana will seek to understand the potential of microRNAs as a tool to distinguish subgroups of AML patients with differing prognoses. The study will pave the way for direct testing of incoming AML cases for aberrant microRNA expressions and will provide guidelines to increase the sample size for next phase of clinical translational research. The outcome will be very important for laying strong framework and foundation for more in-depth and large scale studies with significant clinical implications for AML.

Small Molecule Inhibitors of Twist1 Function to Inhibit Tumor Progression

Douglas Spicer, Ph.D.
Maine Medical Center

The Twist1 gene is highly expressed in many different tumor types and regulates several different stages of tumor development, from initiation through metastasis. Loss of Twist1 can prevent tumor progression, and therefore Twist1 represents a promising target for the development of anti-cancer drugs. Dr. Spicer and his team have identified specific protein interactions that are required for Twist1 function. Consequently this project aims to develop primary and secondary assays for high throughput screening to identify small molecule inhibitors of these interactions and to validate these assays with a small-scale screen of 2,000 compounds. The long-range goal is to extend this initial study to a large-scale screen of more than 500,000 compounds in collaboration with the Broad Institute in Boston. There is now a growing literature on the importance of Twist1 in promoting tumor progression in many different tumor types, and therefore an agent targeting Twist1 function would have broad therapeutic value.

Non-Psychotropic Cannabinoid2 Receptor Agonists Inhibit Breast Cancer Proliferation

Todd W. Vanderah, Ph.D.
University of New England

Breast cancer is the second leading cause of death in women with nearly 200,000 women diagnosed each year in the U.S. Bone is the most common site for breast cancer metastases, resulting in bone loss, fractures, anemia and pain. Despite marked advances in chemotherapy treatments for early stage breast cancer, once the tumor has metastasized to the bone, few new therapies are effective in slowing disease progression and increasing survival in advanced breast cancer patients. Dr. Vanderah’s team at the University of New England is investigating the use of novel compounds that both inhibit the growth of the breast cancer cells and reduce the cancer induced bone pain and bone loss. Their studies so far suggest that these new medicines may provide breast cancer patients a superior alternative to currently available therapeutics.